Practical Application of Circulating Tumor-Related DNA of Human Papillomavirus in Liquid Biopsy to Evaluate the Molecular Response in Patients with Oropharyngeal Cancer

SIMPLE SUMMARY: Oropharyngeal cancer (OPC) is one of the most common cancers in the head and neck region. The incidence of OPC is still growing, mostly due to the human papillomavirus (HPV), which has become the dominant etiological factor. HPV16 is the most relevant genotype for OPC, whereas other high-risk genotypes are rare and may be associated with a worse prognosis. The aim of this article is to discuss the molecular response (MR) obtained by assessing circulating tumor-related HPV DNA (ctHPV) in a liquid biopsy (LB). This quick and simple diagnostic tool reflects the presence of the tumor and thus, can support some clinical decisions. We provide a comprehensive overview of the clinical benefits of the blood-based molecular response, focusing on the decision-making process of the tumor response during the therapy, assessment of early treatment results, and post-treatment follow-up in patients with HPV-related OPC. ABSTRACT: Recent findings have shown that human papillomavirus (HPV) DNA is present in the blood as a tumor-specific biomarker (circulating tumor-related HPV; ctHPV) in patients with HPV-related oropharyngeal cancer (HPV-related OPC). The molecular response (MR) in patients with HPV-related OPC can be defined as the change in the number of ctHPV copies in relation to its initial quantity. The optimal model for assessing the MR using a liquid biopsy (LB) should be based on the E6/E7 sequences of the viral genome. MR assessment can help to evaluate the intensity of ongoing treatments in relation to the tumor response. The evaluation of the residual disease at the end of therapy may also be performed by MR assessment. If a partial MR (pMR) is found, caution is indicated and a subsequent LB should be considered, due to the likelihood of disease progression. Complete radiological and clinical responses together with a complete MR (cMR) convincingly indicate a low risk of treatment failure. Moreover, molecular recurrence (Mrec) during a follow-up, confirmed in two consecutive assays, even despite the lack of any other clinical or radiological symptoms of progression, indicates patients at high risk of disease recurrence. In conclusion, MR by ctHPV assessment may hasten the early detection of disease progression, at any stage of the management of the patient with HPV-related OPC.